Abstract

OBJECTIVE We explore the effect of randomized treatment, comparing intensive to standard glucose-lowering strategies on major cardiovascular
outcomes, death, and severe adverse events in older versus younger participants in the Action to Control Cardiovascular Risk
in Diabetes (ACCORD) trial.

RESEARCH DESIGN AND METHODS Participants with type 2 diabetes (n = 10,251) with a mean age of 62 years, a median duration of diabetes of 10 years, and a median A1C of 8.1% (65 mmol/mol) were
randomized to treatment strategies targeting either A1C <6.0% (42 mmol/mol) or 7.0–7.9% (53–63 mmol/mol) and followed for
a mean of 3.7 years. Outcomes were analyzed within subgroups defined by baseline age (<65 vs. ≥65 years).

RESULTS Older and younger ACCORD participants achieved similar intensive-arm A1C levels and between-arm A1C differences. Within the
older subgroup, similar hazards of the cardiovascular primary outcome and total mortality were observed in the two arms. While
there was no intervention effect on cardiovascular mortality in the older subgroup, there was an increased risk in the intensive
arm for the younger subgroup (older hazard ratio [HR] = 0.97; younger HR = 1.71; P = 0.03). Regardless of intervention arm, the older subgroup experienced higher annualized rates of severe hypoglycemia (4.45%
intensive and 1.36% standard) than the younger subgroup (2.45% intensive and 0.80% standard).

CONCLUSIONS Intensive glucose lowering increased the risk of cardiovascular disease and total mortality in younger participants, whereas
it had a neutral effect in older participants. The intensive to standard relative risk of severe hypoglycemia was similar
in both age subgroups, with higher absolute rates in older participants within both treatment arms.

Introduction

Diabetes prevalence in persons over 65 years old is rapidly increasing, with current estimates varying between 15 and 25%
(1). During the next decade, the greatest increase in diabetes is anticipated to be among persons aged 75 and older (2). Compared with older adults without diabetes, those with diabetes have life expectancy that is reduced by 10 years and double
the mortality (3,4). Reasons for increased mortality and morbidity include cardiovascular, cerebrovascular, and renal diseases and “geriatric”
conditions such as cognitive impairment, physical function decline, disability, depression, incontinence, falls, and the syndrome
of frailty (i.e., fatigue, weight loss, muscle weakness, and decreased overall physical function) (5,6). Despite this increase of diabetes and its complications in older adults, until recently, older adults were poorly represented
in most large diabetes trials. This scenario is similar for many prevalent chronic diseases such as hypertension and cancer
trials, where older adults have until recently been traditionally excluded (7,8).

The under-representation of older adults from initial trials showing the benefits of tight glycemic control led to uncertainty
regarding the applicability and safety of the intervention in older persons (9). More recent glucose-lowering trials such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (10), Action in Diabetes and Vascular Disease (ADVANCE) (11), and the Veterans Affairs Diabetes Trial (12) included older adults; however, they have not reported the effects of the glycemic interventions according to age. Although
the overall benefits were modest and, in some cases, were outweighed by the harms (13), these trials can provide valuable insights into whether older adults can safely tolerate intensive therapy for diabetes.
Although it has been suggested that treatment targets for older persons with long-standing type 2 diabetes may need to be
different (14–16), there is little empiric evidence for such a position. Recommendations for individualization of treatment in older persons
with type 2 diabetes have been based on multiple considerations, including comorbidities, polypharmacy, and patient preferences
(17). However, as a group, little is known regarding the ability of older versus younger individuals to achieve glycemic targets
and the effect of glycemic control on clinically important outcomes.

The purpose of the glycemic portion of the ACCORD study was to determine whether randomization to an intensive therapeutic
strategy targeting normal glycated hemoglobin levels (i.e., below 6.0%, 42 mmol/mol) would reduce the rate of cardiovascular
events, as compared with a standard strategy targeting glycated hemoglobin levels from 7.0 to 7.9% (53–63 mmol/mol) in people
with type 2 diabetes. The ACCORD study previously reported that there were no age-related differences in the effect of the
glycemia intervention on cognition (18), but that the intensive intervention reduced the risk of falls in older individuals and increased it in younger individuals
(RR = 0.75 and 1.27, respectively; P interaction = 0.018) (19). The impact and tolerability of intensive management in older adults (≥65 years old; specifically, 65–89 years old; N = 3,996) versus younger adults (<65 years old; specifically, 40–64 years old; N = 6,255) on glucose control, severe hypoglycemia, severe adverse effects, the ACCORD primary/secondary outcomes, and physical
function (activities of daily living and mobility) are addressed herein. Also addressed is the potentially modifying effect
of age on the previously reported findings that 1) the highest risk in mortality among intensive participants occurred for participants with average postrandomization A1C
>7.0% (53 mmol/mol) and 2) the increased mortality in the intensive arm was most apparent in those participants whose A1C levels fell less rapidly
in the initial year of follow-up (20).

Research Design and Methods

The ACCORD design, CONSORT (Consolidated Standards of Reporting Trials) chart, and major results have been previously published
(10,21–23). The ACCORD trial was a randomized, multicenter, double 2 × 2 factorial trial designed to test the effects on major cardiovascular
disease (CVD) events of intensive versus standard glycemia control (plus either antihypertensive or lipid-lowering intervention
components, which are not addressed in this article). Men and women (N = 10,251) with type 2 diabetes aged 40 to 79 years whose A1C was ≥7.5% (58 mmol/mol) and who had prior evidence of CVD or
additional cardiovascular risk factors were recruited at 77 North American sites. The inclusion/exclusion criteria have been
previously reported (24). Briefly, participants had to have type 2 diabetes with a glycated hemoglobin level of 7.5% or more, be aged 40 to 79 years
with a history of prior CVD, or be aged 55 to 79 years with either anatomical evidence of significant atherosclerosis, albuminuria,
left ventricular hypertrophy, or at least two additional risk factors. Participants with frequent or recent serious hypoglycemic
events, unwillingness to do home glucose monitoring or inject insulin, a BMI of more than 45 kg/m2, a serum creatinine level of more than 1.5 mg/dL (133 mmol/L), or other serious illness were excluded. Participants were
initially recruited into a Vanguard phase of ACCORD (N = 1,184 from January to June 2001), with the subsequent randomization of 9,067 participants taking place from February 2003
to October 2005. In February 2008, the glycemia trial was terminated early due to higher mortality in the intensive compared
with the standard glycemia strategies (10), while the antihypertensive and lipid-lowering components (not discussed here) were continued until Spring 2009.

Clinical Measurements

The primary ACCORD outcome was a composite representing the first occurrence of either nonfatal myocardial infarction (MI)
or nonfatal stroke or cardiovascular death. This outcome, as well as secondary outcomes, including all cause mortality, an
expanded composite comprising the primary outcome plus revascularization or hospitalization for heart failure (congestive
heart failure [CHF]), total (i.e., fatal or nonfatal) MI, total stroke, and fatal or nonfatal CHF (21), were included in the current analysis. Also included were adverse events such as severe hypoglycemia (i.e., requiring assistance)
or an adverse experience that was life threatening and/or resulted in death, permanent disability, hospitalization, or prolongation
of hospitalization.

Two physical function limitations were assessed based on responses to the Health Utilities Index Questionnaire (25), which contains a question that addresses mobility limitations (walking) and another that addresses limitations in the ability
to perform basic activities of daily living. These data were obtained at baseline and 12, 36, and 48 months of follow-up and
coded in terms of having no difficulty versus any difficulty. A1C was collected in each arm at visits scheduled at 4-month
intervals, and the updated average A1C was computed by calculating a weighted average of the cumulative A1C values, with weights
defined by the length of intervals between blood draws (20).

Statistical Analysis

Means and percentages were used to compare baseline characteristics for those <65 versus ≥65 years old at enrollment. Median
A1C was calculated by follow-up month within glycemia and age subgroup. The percentage of participants experiencing hypoglycemia
and other serious adverse events was calculated by glycemia intervention arm. Events per 100 person-years were calculated
by dividing the total number of initial events by the total person-years accrued until either the time of the event or censoring.

Time until the initial occurrence of each of the clinical outcomes was analyzed using Cox proportional hazard (PH) regression
analyses according to the principle of intention to treat. Hazard ratios (HRs) and 95% CIs were derived from these models
within subgroups defined by <65 versus ≥65 years old at enrollment. Analyses were performed for events occurring from randomization
until the date of transition (glycemia substudy: 5 February 2008). Cox PH regression models contained a term representing
glycemia arm allocation plus the following terms accounting for subgroups of participants that were prespecified in the protocol
for analysis of the primary outcome: 1) additional assignment to the blood pressure (BP) or lipid trial, 2) randomization to the intensive BP intervention within the blood pressure trial, 3) randomization to fibrate within the lipid trial, and 4) participants with prior evidence of CVD versus those with no prior CVD. In addition, as done for the ACCORD primary analysis,
a term representing the Clinical Center Network was included for analysis of the primary outcome. For each outcome, the consistency
of the intervention effects within those <65 versus ≥65 years old was assessed within the Cox models using statistical tests
of interactions between the variables representing age and the glycemia intervention. Within those <65 years old and those
≥65 years old, previously described Cox regression models (using penalized B-splines) and Poisson regression models (20), were used to explore the relationship between updated average A1C and mortality risk and to estimate mortality rates in
relation to the magnitude of the 1-year change of A1C within each treatment arm, respectively. For both models, likelihood
ratio tests were used to test for between-subgroup heterogeneity in both the location and shape of lines fitted within glycemia
arms.

A comparison between glycemia arms on the proportion of participants that reported any difficulty in the two functional activities
at each follow-up time was performed using logistic regression and generalized estimating equations, controlling for baseline
difficulty, assignment to the BP or lipid trial, randomization to the intensive BP intervention within the BP trial, and randomization
to fibrate within the lipid trial.

Control of Glycemia

Supplementary Fig. 1 shows the median A1C levels achieved over follow-up through month 80 in the older and younger intensive and standard therapy
glycemia arms. The levels achieved were equivalent for intensive therapy for the older and younger subgroups (median ≈6.4
from months 12–48), but for standard therapy, the median A1C was modestly lower in the older subgroup (median ≈7.5 from months
12–48) compared with the younger subgroup (median ≈7.6 from months 12–48).

Medication Use

An age subgroup comparison of medication used to achieve these levels prior to the transition of intensive participants to
standard therapy identified that a lower percentage of older versus younger intensive glycemia participants were prescribed
metformin (66.6% older, 79.3% younger), any secretagogue (57.7% older, 63.9% younger), and any thiazolidinedione (49% older,
57% younger). Similar percentages of older and younger intensive glycemia participants were placed on any insulin and prandial
insulin. The total dose of insulin was slightly lower in the older versus younger intensive glycemia participants (mean =
0.63 vs. 0.74 units/kg, respectively) and 18.1% of older versus 28.2% of younger intensive glycemia participants were on three
or more classes of medication plus insulin (see Supplementary Table 2). Of final note, older adults had higher rates than younger adults for discontinuation of active management of glycemia medication
regimens by ACCORD physicians at some point during follow-up (11.3 vs. 8.9%, respectively; P = 0.0001). Among older participants, 12.4% in intensive glycemia versus 10.1% in standard glycemia discontinued ACCORD medication
management at least once during follow-up (9.6 vs. 8.2%, respectively, in the younger group).

Adverse Events

As noted in Table 1, participants allocated to intensive glycemic therapy had approximately three times the rate of severe hypoglycemia as those
allocated to standard therapy. This increased risk of hypoglycemia attributable to intensive therapy was similar for the two
age subgroups. However, the absolute annual incidence of severe hypoglycemia was greater for older individuals allocated to
both treatment arms (4.45 and 1.36% in intensive and standard glycemia, respectively) than in younger individuals (2.45 and
0.80% for intensive and standard glycemia, respectively). Over a mean follow-up of 3.7 years, these rates translated into
15.1 and 8.7% of intensively treated older and younger participants, respectively, reporting severe hypoglycemia (5.1 versus
3.0% of older and younger standard glycemia participants, respectively).

Adverse events by glycemia and age subgroup for events occurring before the transition (5 February 2008)

Primary and Secondary Outcomes

As presented in Fig. 1, the effect of the intervention on the primary and all but one of the secondary outcomes was similar across age subgroups.
There was no intervention effect on cardiovascular mortality in the older subgroup (HR = 0.97; 95% CI 0.70–1.36), but an increased
risk in the intensive arm for younger (HR = 1.71; 95% CI 1.17–2.50) versus older participants (P interaction = 0.03). As expected, the older subgroup had higher absolute event rates for all outcomes considered within both
treatment arms. The percentage of participants who were lost to follow-up for outcomes was 3.7% for older adults and 4.1%
for younger adults (P = 0.30).

Functional Limitations as an Outcome

For self-reported difficulty with walking, the percentage of participants reporting difficulty ranged from 30–40% for the
older subgroup and from 27–33% for the younger subgroup, and for difficulty with activity, the percentages ranged from 3.2–7.6%
and 5.9-6.9% within the same age groups, respectively (Fig. 2). The differences between glycemia arms (for either age group) in percentage reporting either difficulty (walking or activity)
were clinically minimal (<2% on an absolute scale).

Plots represent the proportion of participants reporting difficulty with either walking or activities at each follow-up visit.
In the table below the figure, the number of participants providing data at each time point is presented in parentheses, after
the percentage of participants reporting difficulty. M12, month 12; M24, month 24; M36, month 36; M48, month 48; Int, intensive;
Std, standard; Gly, glycemia.

For the walking outcome, we found greater limitations in the intensive arm averaged across time points (P = 0.024) and at the 36-month visit (P = 0.014) for older participants and no differences at 12 months (P = 0.09) or 48 months (P = 0.33). Among younger participants, there were no differences between the glycemia arms across time points (P = 0.06) or at any visit (P = 0.06 for month 12; P = 0.38 at month 36; P = 0.13 at month 48).

For activity limitations, slightly higher levels of limitations existed in the intensive arm within the older subgroup across
time points (P = 0.012) and at the 12-month (P = 0.027) and 48-month (P = 0.042) visits, and no differences were found in activity for younger participants (P = 0.72 overall; P = 0.61 at month 12; P = 0.60 at month 36; P = 0.47 at month 48).

Epidemiological Analysis of Mortality and A1C Levels

Figure 3 contains plots of the relationships between all-cause mortality and both the updated average A1C (Fig. 3A and B) and the initial 12-month fall in A1C (Fig. 3C and D) by age subgroup and intervention arm. Comparing the relationships between Fig. 3A and B, we note that there is no difference between age subgroups in the shape (slope of lines at each updated, average A1C value)
for the intensive (P = 0.38) or standard (P = 0.52) arms; however, the vertical positioning of the lines for the older subgroup are significantly higher within both
intensive (P = 0.01) and standard (P < 0.01) arms. There is a significant difference between the shapes of the intensive and standard lines within Fig. 3A (P = 0.005) but not Fig. 3B (P = 0.06). For both Fig. 3A and B, the confidence intervals for the standard lines for A1C <6.8 completely cover the intensive line, thus limiting conclusions
about differences in this tail of the distribution. The increase in mortality risk within intensively treated participants
was primarily among those with updated average A1C >7.0 (53 mmol/mol), regardless of age subgroup.

Spline curves of the risk of all-cause mortality with the two treatment strategies. A and B: The linear part of the PH model for average A1C from 6.0 to 9.0% (42 to 75 mmol/mol) for participants aged <65 and ≥65 years
at randomization, respectively. For clarity, the figure omits values <6 (42 mmol/mol) and >9% (75 mmol/mol); approximately
5% of deaths are excluded from the plot at the lower and also at the higher end of the A1C range, but these data are included
in the models. The plotted values are relative to a standard participant, aged <65 years at randomization and at an A1C of
6%. The dashed lines represent estimates and CIs for standard participants, solid lines are for intensive participants. C and D: The results from a Poisson regression model of all-cause mortality rates by treatment and age subgroup for the whole period
of follow-up, over a range of decreases in A1C from baseline in the first year of treatment (as %A1C). The figures omit values
beyond the 5th and 95th percentiles of A1C changes. The full range of values was from 6.8% (51 mmol/mol; an increase) to 7.4%
(57 mmol/mol; a decrease) from baseline. The calculations used a Poisson regression model with data from model 3 of Riddle
et al. (20).

When relating mortality risk to the initial 12-month fall in A1C (Fig. 3C and D), we could not conclude that the shape of the lines between the two age subgroups were different within intensive (P = 0.24) or standard (P = 0.23) arms; however, the location of the lines were higher for older participants in both intensive (P = 0.03) and standard (P < 0.01) arms. Within age groups, the shapes of intensive and standard curves were not different within Fig. 3C (P = 0.79) but were different within Fig. 3D (P = 0.003). While the older subgroup that was treated intensively displays a large elevation in the mortality rate for those
with little reduction in A1C levels (Fig. 3D), this elevation must be considered within the context of the variability in estimates; only 6 deaths and 219 person-years
of follow-up occurred among intensive participants with an increase in A1C during the initial 12 months.

Conclusions

Overall, our analysis of the impact of baseline age on the effect of more intensive blood glucose lowering in the ACCORD trial
indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic (e.g., attained
A1C targets) and primary and secondary end point effects in older and younger participants. These results illustrate that
age is not a primary factor in success of achieving glycemia treatment targets within the age range included in ACCORD. Similarly,
the ADVANCE study found that the effect of intensive glycemic control on the primary outcome of major cardiovascular events
was comparable within younger and older age subgroups (11). These results are analogous to findings such as those of the SHEP (Systolic Hypertension in the Elderly Program) study
that contradicted commonly held beliefs that older adults would not tolerate targeted BP reduction as well as younger patients
with hypertension (26).

Compared with standard therapy, ACCORD’s intensive glycemia strategy resulted in a higher incidence of cardiovascular mortality
in the younger participants but not in older participants (P = 0.03 for interaction). A similar trend between younger and older participants was seen for total mortality (P = 0.10). As might be expected, the absolute incidence of outcome and adverse events was generally greater in the older compared
with the younger subgroup.

It has been previously suggested that older adults may be more susceptible to hypoglycemic episodes (27–29). ACCORD investigators and others have shown that that there are definable subgroups of older adults, such as those persons
with evidence of early cognitive impairment (30) or dementia (31), who are at greatest risk for serious treatment side effects such as hypoglycemia. Our results now amplify prior findings
in older patients. In ACCORD, older adults were at higher risk of hypoglycemia than younger adults, and intensive glycemic
therapy appeared to triple the risk in both older (4.45% intensive and 1.36% standard annualized risk) and younger (2.45%
intensive and 0.80% standard annualized risk) adults. In the older group, over a mean follow-up of 3.7 years, these rates
translated into a total of 15.1% intensive and 5.1% standard arm participants reporting severe hypoglycemia. The trend for
increased hypoglycemia risk among older participants was identified early during ACCORD follow-up in those ≥80 years old at
randomization, where early monitoring of hypoglycemia rates by the external data and safety monitoring board (DSMB) identified
elevated rates of hypoglycemia in participants who were ≥80 years old at randomization. The ACCORD DSMB recommended at their
May 2003 meeting that no additional participants over 80 years old be recruited into the main ACCORD trial, and this recommendation
was quickly implemented. At that time, among the 1,184 Vanguard participants followed for an average of 1.8 years (1,150 were
<80 years old, 34 were 80+ years old), 20.5% of those ≥80 years old and 4.7% of those <80 years old had reported hypoglycemia
requiring emergency medical assistance.

Two hypotheses set forth for the increased mortality in participants treated intensively for glycemia have involved the speed
of decline in A1C (20) and the increase in hypoglycemia rates (32). In epidemiologic analyses, Riddle et al. (20) have shown that the highest rates of mortality in the intensive arm was in the subgroup of participants with the least rapid
drop in A1C levels during the initial 12-months of follow-up. The elevated mortality risk associated with less A1C decline
in the initial 12 months was most prominent in those in the older subgroup (see Fig. 3). However, any inference regarding glycemia treatment differences in these figures should be severely restricted due to the
variability in estimates at the tails of the distributions. Regarding hypoglycemia, Bonds et al. (32) were unable to directly link higher rates of severe hypoglycemia in the intensive arm to the overall increased risk of mortality
in intensively treated participants. Notably, our analyses identified no increase in total mortality risk associated with
intensive therapy compared with standard therapy among older participants (HR = 1.06) but a similar relative increase in risk
of hypoglycemia for intensive versus standard treated participants for older and younger participants (approximately 3.0 in
both subgroups). In addition, the neutral effect of allocation to the intensive treatment on mortality in older participants
did not appear to be due to the slightly higher rate of discontinuation of ACCORD medication management in this group (unreported
analyses). Finally, because a wide range of glycemic approaches were used and individually tailored to participant characteristics,
epidemiologic analyses of ACCORD medications data may be unable to detect small but important relationships within subgroups.

These results should be viewed as hypothesis generating and interpreted with caution since they are tertiary analyses for
the ACCORD trial involving subgroups, some of which may be quite small (33). Specifically, the demographic differences between the two age groups relative to gender, racial composition, and other
characteristics should also be noted relative to the patient populations for whom these subgroup analyses apply. Finally,
ACCORD was designed to include only community-dwelling ambulatory participants; thus these results cannot be applied to more
frail and disabled or institutionalized groups of older adults.

In summary, while we have shown that similar glycemic levels can be reached in ambulatory, community-dwelling older and younger
adults, the frequency of serious adverse events associated with intensive targets was consistently higher within the older
subgroup. The increased risk of hypoglycemia in older versus younger adults, regardless of whether they were in intensive
or standard therapy, also suggests the need to individualize therapy in older adults with type 2 diabetes, as suggested by
others (15,34,35). The recent 2012 American Diabetes Association Consensus Report emphasizes a need to stratify targets based on comorbid
illness and functional status, among other factors, rather than on age alone (17). Where the ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment
older adults, there is little evidence to suggest that older adults received a CVD benefit. Importantly, the ACCORD glycemia
experience supports the concept that older adults should be included in clinical trials along with careful monitoring of adverse
effects. Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring
of future clinical trials that include older patients with type 2 diabetes and other chronic diseases.

Funding. This work was supported by National Heart, Lung, and Blood Institute contracts N01-HC-95178, N01-HC-95179, N01-HC-95180,
N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA #Y1-HC-9035, and IAA#Y1-HC-1010. Other components of the National
Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute
on Aging, and the National Eye Institute, contributed funding. The Centers for Disease Control and Prevention funded substudies
within ACCORD on cost-effectiveness and health-related quality of life. General Clinical Research Centers provide support
at many sites. The work of M.E.M., J.D.W., and W.B.A. was partially supported by the Wake Forest University Claude D. Pepper
Older Americans Independence Center (P30-AG21332).

The donors of medications and devices had no role in the study design, data accrual and analysis, or manuscript preparation.

Author Contributions. M.E.M. and L.L. researched data and wrote the manuscript. J.D.W., H.C.G., R.P.B., W.C.C., and H.N.G. reviewed and edited
the manuscript. W.T.A. researched the data. W.B.A. wrote the manuscript. M.E.M. is the guarantor of this work and, as such,
had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the
data analysis.

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